Creating and comprehending the circuitry of life: precise biomolecular design of multi-centre redox enzymes for a synthetic metabolism

创建和理解生命回路:用于合成代谢的多中心氧化还原酶的精确生物分子设计

基本信息

  • 批准号:
    BB/W003449/1
  • 负责人:
  • 金额:
    $ 499.44万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

A defining characteristic of life is the requirement of energy from an external source; we eat, plants absorb light. To maximize the energy gained from the food that we and all oxygen-breathing organisms consume, oxygen is converted to water as a final step and carbon dioxide is released. The oxygen in this equation arises from plants as they convert water, carbon dioxide and light, into oxygen and fuel. This cycle is not merely an auspicious result of billions of years of evolution. The molecular events that allow the processes of respiration and photosynthesis to happen are connected in deep ways, down to shared structures, molecules, and mechanisms.At their most basic, respiration and photosynthesis are Nature's way to capture and convert energy from one form to another. To do this, Nature has evolved complex structures, termed oxidoreductases, that bind molecules that aid in this conversion. These molecules can both absorb light, imparting plants with their colours, and take and give electrons. The oxidoreductases have evolved to take energy from external sources and convert it into forms that can be used by living organisms to grow and survive. The evident complexity of this process belies a central feature of the oxidoreductases involved: evolution has yielded structures that are built from repeats of relatively simple modules. All of respiration and photosynthesis are built on these repeating modules. But despite nearly a century of investigation, where we have outlined how respiration and photosynthesis work in fine detail, we remain unable to construct our own models of these processes. This naturally leads to a question of whether we really understand how these processes occur. Here we have assembled a team of researchers from multiple academic institutions and disciplines to address deficiencies in our knowledge, with the unified target of building completely new oxidoreductases from scratch. Through this work we will fill holes in our understanding of how Nature captures and converts energy. Our work begins by combining powerful computational techniques that allow us to design and construct oxidoreductases with tailor made functions. Within a virtual reality framework that we are developing for this project, we will work together in a shared digital space to construct molecular binding sites, alter how molecules take and give electrons or catalyse reactions, and create oxidoreductase modules that, taking inspiration from Nature, we will join to produce more complex functions. With these designs, we will use an iterative 'build-test-learn' approach to construct new oxidoreductases that match the activities and actions of those Nature uses in respiration and photosynthesis. By pulling together our expertise in computational biophysical methods, oxidoreductase engineering, modular structure creation, molecular binding site assembly and their chemistry, and the analysis of very fast oxidoreductase functions, our team stands to make a substantial leap in our understanding of how to construct new oxidoreductases that has, so far, remained beyond our grasp. The principles we establish through this work will help us to better understand the oxidoreductases of respiration and photosynthesis, finally clarifying architectural features that are essential for their assembly and function that have remained opaque for over a century. With our new sets of design principles, we will be able to create oxidoreductases that fulfil our needs in bioscience and biotechnology, from the creation of single structures that produce fuels from light, water and carbon dioxide akin to photosynthesis to biosensors that detect toxins in the environment or signs of disease.
生命的一个决定性特征是需要来自外部来源的能量;我们吃东西,植物吸收光。为了最大限度地从我们和所有呼吸氧气的生物体消耗的食物中获得能量,氧气转化为水作为最后一步,二氧化碳被释放出来。这个等式中的氧气来自植物,因为它们将水,二氧化碳和光转化为氧气和燃料。这个周期不仅仅是数十亿年进化的吉祥结果。呼吸作用和光合作用的分子过程是相互关联的,它们的结构、分子和机制都是相同的。最基本的,呼吸作用和光合作用是自然界捕获能量并将能量从一种形式转化为另一种形式的方式。为了做到这一点,自然界已经进化出复杂的结构,称为氧化还原酶,它结合有助于这种转化的分子。这些分子既可以吸收光,赋予植物颜色,又可以吸收和释放电子。氧化还原酶已经进化到从外部来源获取能量并将其转化为可供生物体生长和生存的形式。这一过程的明显复杂性掩盖了所涉及的氧化还原酶的一个核心特征:进化产生了由相对简单模块的重复构建的结构。所有的呼吸和光合作用都建立在这些重复的模块上。但是,尽管经过近世纪的研究,我们已经详细地描述了呼吸和光合作用的工作原理,但我们仍然无法构建自己的模型。这自然会引出一个问题,即我们是否真正了解这些过程是如何发生的。在这里,我们组建了一个来自多个学术机构和学科的研究人员团队,以解决我们知识中的不足,统一的目标是从头开始构建全新的氧化还原酶。通过这项工作,我们将填补我们对大自然如何捕获和转换能量的理解中的漏洞。我们的工作开始于结合强大的计算技术,使我们能够设计和构建具有定制功能的氧化还原酶。在我们为这个项目开发的虚拟现实框架内,我们将在一个共享的数字空间中共同构建分子结合位点,改变分子如何获取和提供电子或催化反应,并创建氧化还原酶模块,从自然界中汲取灵感,我们将加入以产生更复杂的功能。通过这些设计,我们将使用迭代的“构建-测试-学习”方法来构建新的氧化还原酶,这些酶与自然界在呼吸和光合作用中使用的活性和作用相匹配。通过将我们在计算生物物理方法,氧化还原酶工程,模块化结构创建,分子结合位点组装及其化学,以及快速氧化还原酶功能分析方面的专业知识结合在一起,我们的团队将在我们对如何构建新的氧化还原酶的理解方面取得重大飞跃,到目前为止,仍然超出了我们的掌握范围。我们通过这项工作建立的原则将帮助我们更好地了解呼吸和光合作用的氧化还原酶,最终澄清建筑特征,这些特征对于它们的组装和功能至关重要,这些特征在世纪以来一直不透明。通过我们新的设计原理,我们将能够创造出满足我们在生物科学和生物技术方面需求的氧化还原酶,从创造类似于光合作用的光、水和二氧化碳产生燃料的单一结构到检测环境中毒素或疾病迹象的生物传感器。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations.
  • DOI:
    10.1021/acs.jctc.3c00785
  • 发表时间:
    2024-01-09
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Oliveira, A. S. F.;Rubio, J.;Noble, C. E. M.;Anderson, J. L. R.;Anders, J.;Mulholland, A. J.
  • 通讯作者:
    Mulholland, A. J.
Cellular production of a de novo membrane cytochrome.
Heme binding to the SARS-CoV-2 spike glycoprotein.
  • DOI:
    10.1016/j.jbc.2023.105014
  • 发表时间:
    2023-08
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Freeman, Samuel L.;Oliveira, A. Sofia F.;Gallio, Andrea E.;Rosa, Annachiara;Simitakou, Maria K.;Arthur, Christopher J.;Mulholland, Adrian J.;Cherepanov, Peter;Raven, Emma L.
  • 通讯作者:
    Raven, Emma L.
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Ross Anderson其他文献

Blackbox Attacks on Reinforcement Learning Agents Using Approximated Temporal Information
使用近似时间信息对强化学习代理进行黑盒攻击
The Unlucky Voyage: Batavia’s (1629) Landscape of Survival on the Houtman Abrolhos Islands in Western Australia
不幸的航行:巴达维亚(1629)西澳大利亚霍特曼阿布罗霍斯群岛的生存景观
  • DOI:
    10.1007/s41636-023-00396-1
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0.8
  • 作者:
    A. Paterson;Jeremy Green;Wendy van Duivenvoorde;D. Franklin;Ambika Flavel;L. Smits;J. Shragge;M. Manders;C. Souter;D. Shefi;Ross Anderson;T. Hoskin;Nader Issa;Mike Nash
  • 通讯作者:
    Mike Nash
Experimental investigation of methane hydrate growth and dissociation hysteresis in narrow pores
窄孔隙中甲烷水合物生长和解离滞后的实验研究
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ross Anderson;M. Cueto;B. T. Kalorazi
  • 通讯作者:
    B. T. Kalorazi
Hextend and 7.5% hypertonic saline with Dextran are equivalent to Lactated Ringer's in a swine model of initial resuscitation of uncontrolled hemorrhagic shock.
Heextend%20和%207.5%%20高渗%20盐水%20和%20葡聚糖%20是%20当量%20至%20乳酸%20林格氏%20in%20a%20猪%20模型%20of%20初始%20复苏%20of%20不受控制%20出血%20休克。
  • DOI:
    10.1097/ta.0b013e3182367b1c
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    G. Riha;Nicholas R. Kunio;Philbert Y. Van;Gregory J. Hamilton;Ross Anderson;J. Differding;M. Schreiber
  • 通讯作者:
    M. Schreiber
A Wet Cold-Flow Technology for Tackling Offshore Flow-Assurance Problems
用于解决海上流量保证问题的湿冷流技术
  • DOI:
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    0
  • 作者:
    R. Azarinezhad;A. Chapoy;Ross Anderson;B. Tohidi
  • 通讯作者:
    B. Tohidi

Ross Anderson的其他文献

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{{ truncateString('Ross Anderson', 18)}}的其他基金

Tracking Covid Cybercrime and Abuse
追踪 Covid 网络犯罪和滥用行为
  • 批准号:
    EP/V026178/1
  • 财政年份:
    2020
  • 资助金额:
    $ 499.44万
  • 项目类别:
    Research Grant
Constructing catalytically proficient enzymes from de novo designed proteins
从头设计的蛋白质构建催化效率高的酶
  • 批准号:
    BB/R016445/1
  • 财政年份:
    2018
  • 资助金额:
    $ 499.44万
  • 项目类别:
    Research Grant
Interdisciplinary Centre for Finding, Understanding and Countering Crime in the Cloud
寻找、理解和打击云端犯罪的跨学科中心
  • 批准号:
    EP/M020320/1
  • 财政年份:
    2015
  • 资助金额:
    $ 499.44万
  • 项目类别:
    Research Grant
Building Solar-Powered, Carbon-Fixing Protoalgae
构建太阳能固碳原藻
  • 批准号:
    BB/M02315X/1
  • 财政年份:
    2015
  • 资助金额:
    $ 499.44万
  • 项目类别:
    Research Grant
The Deterrence of Deception in Socio-Technical Systems
社会技术系统中欺骗的威慑
  • 批准号:
    EP/K033476/1
  • 财政年份:
    2013
  • 资助金额:
    $ 499.44万
  • 项目类别:
    Research Grant
Assembly of Artificial Oxidoreductases
人工氧化还原酶的组装
  • 批准号:
    BB/I014063/1
  • 财政年份:
    2011
  • 资助金额:
    $ 499.44万
  • 项目类别:
    Research Grant
Measuring the Security of Internet Infrastructure
衡量互联网基础设施的安全性
  • 批准号:
    EP/H018298/1
  • 财政年份:
    2010
  • 资助金额:
    $ 499.44万
  • 项目类别:
    Research Grant

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Comprehending the intracellular mechanotransduction system by 3D mechano-mapping of the cytoskeleton
通过细胞骨架的 3D 力学映射理解细胞内力学转导系统
  • 批准号:
    23K18135
  • 财政年份:
    2023
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    $ 499.44万
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    Grant-in-Aid for Challenging Research (Exploratory)
CISE-ANR: SHF: Small: CHAMELEON: CompreHending And Mitigating Error in AnaLog ImplEmentations of On-Die Neural Networks
CISE-ANR:SHF:小:CHAMELEON:理解并减轻片上神经网络模拟实现中的错误
  • 批准号:
    2214934
  • 财政年份:
    2022
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    $ 499.44万
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    Standard Grant
Quantitative mass spectrometry for comprehending epigenetic mechanisms in a new underlying neurological developmental disorder
定量质谱分析用于理解新的潜在神经发育障碍的表观遗传机制
  • 批准号:
    10515832
  • 财政年份:
    2022
  • 资助金额:
    $ 499.44万
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Quantitative mass spectrometry for comprehending epigenetic mechanisms in a new underlying neurological developmental disorder
定量质谱分析用于理解新的潜在神经发育障碍的表观遗传机制
  • 批准号:
    10684772
  • 财政年份:
    2022
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    $ 499.44万
  • 项目类别:
Mechanisms for comprehending different English accents: focus on Asian and African varieties
理解不同英语口音的机制:关注亚洲和非洲口音
  • 批准号:
    21H00533
  • 财政年份:
    2021
  • 资助金额:
    $ 499.44万
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    Grant-in-Aid for Scientific Research (B)
Comprehending the range of the mangrove rhizosphere - An investigation of plants effects on soil nitrogen dynamics at high spatial resolution
了解红树林根际范围 - 高空间分辨率下植物对土壤氮动态影响的研究
  • 批准号:
    20H03029
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CAREER: Collaboratively Perceiving, Comprehending, and Projecting into the Future: Supporting Team Situational Awareness with Adaptive Multimodal Displays
职业:协作感知、理解和预测未来:通过自适应多模态显示支持团队态势感知
  • 批准号:
    2008680
  • 财政年份:
    2019
  • 资助金额:
    $ 499.44万
  • 项目类别:
    Continuing Grant
CRII: CHS: Collaboratively Perceiving, Comprehending, and Projecting into the Future: Supporting Team Situational Awareness with Adaptive Collaborative Tactons
CRII:CHS:协作感知、理解和预测未来:通过自适应协作 Tactons 支持团队态势感知
  • 批准号:
    2002348
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    2019
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    $ 499.44万
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    Standard Grant
Comprehending text: A natural laboratory for investigating cognitive ageing
理解文本:研究认知衰老的自然实验室
  • 批准号:
    DP180102705
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    2018
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CAREER: Collaboratively Perceiving, Comprehending, and Projecting into the Future: Supporting Team Situational Awareness with Adaptive Multimodal Displays
职业:协作感知、理解和预测未来:通过自适应多模态显示支持团队态势感知
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    1750850
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    2018
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